The primary goal of this Career Development Award (K99/R00) is to provide protected time for the candidate to obtain the necessary training and mentoring to establish an independent clinical research program for understanding physiological and psychological mechanisms underlying pain modulation and how these mechanisms contribute to Temporomandibular Joint Disorder (TMJD). The current proposal extends the candidate's previous background in stress and pain psychophysics with additional training to investigate physiological and psychological factors involved in the pathophysiology of TMJD. Specific training areas in the mentored phase of the K99 will help the candidate achieve several short-term goals including developing expertise in psychoneuroimmunology (PNI), psychological theory and assessment, and clinical exposure through guided mentorship, didactic coursework, and applied research experiences in healthy controls (HC) and in patients with TMJD. In addition, the training will establish the candidate as an independent clinical researcher by increasing his productivity, which will assist in obtaining a tenure-track faculty position and independent funding. Long term goals of the training include establishing an independent research laboratory to investigate physiological and psychological factors mediating clinical and experimental pain. The mentored phase of the K99 will take place at the University of Florida College of Dentistry under the direct mentorship of Dr. Roger Fillingim, Ph.D. and co-mentorship of Dr. Joseph Riley, Ph.D., both mentors are nationally and internationally respected experts in the field of pain and orofacial research. The environment is ideal for this project because the university places a strong emphasis on pain research including orofacial pain. The necessary laboratory, equipment, and supplies needed to complete the series of studies described in this proposal are available to the candidate. The research plan offers a series of studies that are designed to elucidate factors mediating the reduced efficacy of endogenous pain inhibition TMJD patients based on a model of conditioned pain modulation (CPM). In this model, pain inhibition is characterized by a reduction of heat pain sensitivity during exposure to a tonic conditioning stimulus. While the mechanisms remain unknown, the reduced pain inhibitory capacity in TMJD could be due to a maladaptive stress system, which is influenced by abnormal physiological (i.e., endogenous opioids, cholecystokinin) and psychological (i.e., catastrophizing) responses to pain. The research plan will use the skills developed during the career plan to investigate the impact of maladaptive neuroendocrine and pro-inflammatory immune responses and negative psychological reactions as important factors in reduced pain inhibition in TMJD. These observations will be accomplished by cross-sectional evaluations (Aim 1) and experimental manipulations of pain expectation (Aim 2). The candidate will use the skills and knowledge gained during the mentored training phase (K99) to transition to the independent (R00) phase. Aim 3 will investigate the interactions of endogenous opioid and cholecystokinin systems with psychological and biological responses to pain. The proposed series of studies will provide a more thorough understanding of endogenous pain modulation in patients who suffer with TMJD. Since it is the goal of the National Institute of Dental and Craniofacial Research (NIDCR) to understand the causes of orofacial pain, the mechanisms underlying endogenous pain inhibition are a potential target that could assist in development of therapies to prevent and treat TMJD.